KRAS Codon 12 and Codon 13 Mutations in Relation to Overall Survival among Colorectal Cancer Patients: A Systematic Review and Meta-Analysis

Oncogenic mutations in KRAS codon 12 and codon 13 within exon 2 are frequently occurring mutations in colorectal cancer (CRC). However, the existing published data on the association of KRAS codon 12 and codon 13 mutations on the survival of CRC patients remains inconclusive. To address this, we conducted a systematic PubMed search and meta-analysis. Random-effects models were employed to quantify pooled association estimates and to investigate heterogeneity. Meta-regression was performed to examine sources of heterogeneity followed by subgroup analyses stratified by variables that significantly impact survival estimates. In total, this study involved a review of 502 articles, with 46 studies included in the meta-analysis. Compared to individuals with KRAS wild-type CRC, those CRC exhibiting a KRAS codon 12 or codon 13 mutation experienced significantly poorer overall survival (OS) [pooled hazard ratio (HR) = 1.40, 95% confidence interval (CI): 1.32–1.49], with heterogeneity in point estimates across studies (p-het = 0.0006). Meta-regression showed that whether or not study-specific estimates were adjusted for microsatellite instability (MSI) status explained part of this heterogeneity (p < 0.01) and revealed that associations were more modest in the presence of adjustment for MSI status (pooled HR = 1.21, 95% CI: 1.07–1.36, 9 studies, p-het = 0.09) and stronger in the absence of MSI status adjustment with evidence of remaining heterogeneity (pooled HR = 1.45, 95% CI: 1.37–1.54, 37 studies, p-het = 0.03). Further meta-regression among these 37 studies not adjusted for MSI status showed that whether or not study-specific estimates were adjusted for stage explained part of the heterogeneity (p = 0.01) and showed that the associations were stronger among studies that adjusted for stage (pooled HR = 1.61, 95% CI: 1.45–1.79, 10 studies, p-het = 0.40) than among the studies that did not adjust for stage (pooled HR = 1.39, 95% CI: 1.30–1.48, 27 studies, p-het = 0.11). Overall, somatic KRAS codon 12 and codon 13 mutations were significantly associated with poorer OS, and results varied depending on whether studies adjusted for MSI status and stage, supporting the prognostic significance of these mutations in patients with CRC.